Clinical, neuropathological, and genetic characterization ofSTUB1variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Purpose Pathogenic variants inSTUB1were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). Methods We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. Results STUB1variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% ofSTUB1variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while noSTUB1variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of aSTUB1heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening ofSTUB1variants revealed new features: (1) the majority of patients were women (70%) and (2) ``second hits'' inAFG3L2,PRKCG, andTBPwere detected in three families suggesting synergic effects. Conclusion Our results reveal an unexpectedly frequent (7%) implication ofSTUB1among dominantly inherited cerebellar ataxias, and suggest that the penetrance ofSTUB1variants could be modulated by other factors, including sex and variants in other ataxia-related genes.